AB0619 Rationale and Design of the 52-week, Randomized, Phase 3, Head-to-Head MANDARA Study to Evaluate the Efficacy and Safety of Benralizumab, a Humanized, Anti-interleukin–5 Receptor α Monoclonal Antibody in Refractory or Relapsing Eosinophilic Granulomatosis with Polyangiitis
Authors: M. Wechsler, P. A. Merkel, S. Necander, L. Börjesson Sjö, E. A. Duncan, N. Makulova, G. D’angelo, R. A. Chen, V. H. Shih, R. Katial, U. J. Martin
Journal: Annals of the Rheumatic Diseases (2022)

Background Eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss syndrome) is a rare, potentially organ- and life-threatening disease characterized by systemic eosinophilia, airway disease, and multi-system small-vessel vasculitis. Management of EGPA generally focuses on reducing active inflammation using corticosteroids and immunosuppressants, both of which are associated with serious adverse effects and incomplete disease control. High blood eosinophil (bEOS) levels are a central component of the pathophysiology of EGPA, and studies have shown that bEOS-reducing therapies, such as mepolizumab, are effective in some patients with EGPA. Benralizumab is a humanized, afucosylated, anti-interleukin-5 receptor α monoclonal antibody that induces direct, rapid, and near complete depletion of eosinophils through antibody-dependent cell-mediated cytotoxicity. Eosinophil depletion by benralizumab is effective in eosinophilic asthma, corticosteroid-dependent asthma, and has shown promise in a small phase 2 trial in hypereosinophilic syndrome, which has overlapping organ systems involvement and similar clinical features to EGPA. Collectively, the evidence from these indications supports examination of the efficacy of benralizumab as an eosinophil-depleting therapy in patients with EGPA. Objectives The phase 3, head-to-head MANDARA ( NCT04157348 ) study will evaluate the efficacy and safety of benralizumab versus mepolizumab in adults with relapsing or refractory EGPA. Methods This randomized (1:1), multicentre, double-blind (DB), active-controlled study is enrolling adults with a diagnosis of EGPA, defined as a history of asthma and eosinophilia together with ≥2 additional clinical features, a history of relapsing or refractory disease, and maintained on a stable prednisolone/prednisone dose ≥7.5 mg/day for ≥4 weeks prior to baseline. Patients will receive either benralizumab 30 mg or mepolizumab 300 mg every 4 weeks over the 52-week DB study period. Patients who complete the DB treatment period will be eligible to continue into an optional open-label extension, during which all patients will receive benralizumab (Figure 1). The primary endpoint is the proportion of patients who achieve EGPA remission, defined as a Birmingham Vasculitis Activity Score (BVAS)=0 and prednisolone dose of ≤4 mg/day, at both Week 36 and 48 of the DB period, and it will assess non-inferiority (NI) between benralizumab and mepolizumab. Secondary endpoints include duration of remission, time to first EGPA relapse, annualized relapse rate, average daily prednisolone dose between Weeks 48 to 52, and the proportion of patients who achieve and maintain remission from Week 24 through the end of the DB period. Other endpoints include safety, symptoms, health-related quality of life, healthcare utilization due to EGPA, and tolerability. The trial also includes a non-interventional patient interview sub-study, which will collect data related to patients’ EGPA personal experience and perceived impact on study treatment, and a mechanistic sub-study, which will explore the pharmacodynamic response and mechanism of action of benralizumab compared to mepolizumab. Figure 1. MANDARA Study Design Results The study aims to enrol 140 patients which will provide ~90% power to demonstrate NI with a NI margin of -25% at the 2.5% one-sided significance level, assuming each treatment group has a remission rate of 32%. Screening started in Oct 2019 and the trial is ongoing. Conclusion MANDARA is one of few multicentre randomized trials conducted to date in EGPA. Results from this phase 3, head-to-head study will characterize the efficacy and safety of benralizumab compared with mepolizumab in adults with relapsing or refractory EGPA. The trial’s active comparator design will also provide critical evidence of efficacy and safety in a disease with considerable unmet needs. Disclosure of Interests Michael Wechsler Speakers bureau: GlaxoSmithKline, AstraZeneca, Amgen, Sanofi, Regeneron, Novartis, Genentech, and Teva Pharmaceuticals, Grant/research support from: GlaxoSmithKline, AstraZeneca, Amgen, Sanofi, Regeneron, Novartis, Genentech, and Teva Pharmaceuticals, Peter A. Merkel Consultant of: AbbVie, AstraZeneca, Boeringher-Ingelheim, Bristol-Myers Squibb, ChemoCentryx, CSL Behring, Dynacure, EMDSerono, Forbius, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, InflaRx, Janssen, Kiniksa, Kyverna, Magenta, MiroBio, Neutrolis, Novartis, Pfizer, Sparrow, Takeda, Talaris, Grant/research support from: AbbVie, AstraZeneca, Boeringher-Ingelheim, Bristol-Myers Squibb, ChemoCentryx, Eicos, Forbius, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, InflaRx, Sanofi, Sofia Necander Shareholder of: AstraZeneca, Employee of: AstraZeneca, Lena Börjesson Sjö Shareholder of: AstraZeneca, Employee of: AstraZeneca, Elizabeth A. Duncan Shareholder of: AstraZeneca, Employee of: AstraZeneca, Natalya Makulova Shareholder of: AstraZeneca, Employee of: AstraZeneca, Gina D’Angelo Shareholder of: AstraZeneca, Employee of: AstraZeneca, Ron A. Chen Shareholder of: AstraZeneca, Employee of: AstraZeneca, Vivian H. Shih Shareholder of: AstraZeneca, Employee of: AstraZeneca, Rohit Katial Shareholder of: AstraZeneca, Employee of: AstraZeneca, Ubaldo J. Martin Shareholder of: AstraZeneca, Employee of: AstraZeneca